The goal of this Program Project application, entitled "Signal Transduction in Time and Space", is to understand cell signaling by cell surface receptors, protein and lipid kinases, phosphatases and GTPases within the context of a four dimensional process, organized and expedited by the actin cytoskeleton, adapter proteins and targeting molecules. Understanding how signals are propagated in time and space requires the identification of novel molecular scaffolds required for targeting molecules toward defined intracellular compartments, new experimental approaches for measuring signals generated in intracellular compartments, and a better understanding of the dynamics of signal propagation and regulation. The spatial and temporal analysis of signal transduction is fundamental to understanding normal cellular regulation and critical to understanding abnormal cellular signaling processes, central hallmarks of cancer cells. The Program Project endeavors to facilitate the analysis of cellular signaling in time and space by fostering a highly interactive environment, one in which exchanges of ideas, expertise and technical resources occur freely and efficiently in time and space. In the first Project, Parsons and Horwitz focus on understanding the role of protein tyrosine kinases and small GTPases in the spatial and temporal regulation of cell adhesion assembly and turnover. In the second Project, Brautigan and Eto will examine how targeting subunits of cellular phosphatases localize to sites of dynamic reorganization, such as adhesion complexes and cell-cell junctions. These proteins are activated by phosphorylation and integrate multiple signals to control actin organization in cells, a key step in mobilizing the tensional forces needed to drive cell migration and cell polarization. The Program is supported by aMicroscopy Core that provides cutting edge imaging capabilities, image analysis and training to the Program.